Essentials of Clinical Immunology

Helen Chapel, Mansel Haeney, Siraj A. Misbah, Neil Snowden

• Publisher: Wiley-Blackwell
• Year: 2013
• ISBN:
  9781118487877
• Edition: 6
• Topic: Medicina
• Subtopic: Medicina pulmonar y torácica

Essentials of Clinical Immunology provides the most up-to-date, core information required to understand diseases with an immunological basis. Clinically focussed, the sixth edition of this classic text presents theoretical and practical information in a simple yet thorough way. Essentials of Clinical Immunology covers the underlying pathophysiology, the signs and symptoms of disease, the investigations required and guidance on the management of patients. Perfect for clinical medical students, junior doctors and medical professionals seeking a refresher in the role of immunology in clinical medicine, this comprehensive text features fully updated clinical information, boxes with key points, real-life case histories to illustrate key concepts and an index of contents at the start of each chapter. A companion website at www.immunologyclinic.com provides additional learning tools, including more case studies, interactive multiple-choice questions and answers, all of the photographs and illustrations from the book, links to useful websites, and a selection of review articles from the journal Clinical and Experimental Immunology. This title is also available as a mobile App from MedHand Mobile Libraries. Buy it now from iTunes, Google Play or the MedHand Store.

Chapter 1

Basic Components: Structure and Function

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Key topics

• 1.1 Introduction
• 1.2 Key molecules
  • 1.2.1 Molecules recognized by immune systems
  • 1.2.2 Recognition molecules
  • 1.2.3 Accessory molecules
  • 1.2.4 Effector molecules for immunity
  • 1.2.5 Receptors for effector functions
  • 1.2.6 Adhesion molecules
• 1.3 Functional basis of innate responses
  • 1.3.1 Endothelial cells
  • 1.3.2 Neutrophil polymorphonuclear leucocytes
  • 1.3.3 Macrophages
  • 1.3.4 Dendritic cells
  • 1.3.5 Complement
  • 1.3.6 Antibody-dependent cell-mediated cytotoxicity
  • 1.3.7 Natural killer cells
• 1.4 Functional basis of the adaptive immune responses
  • 1.4.1 Antigen processing
  • 1.4.2 T cell mediated activation responses
  • 1.4.3 Antibody production
• 1.5 Physiological outcomes of immune responses
  • 1.5.1 Killing of target cells (virally infected/tumour cells)
  • 1.5.2 Direct functions of antibody
  • 1.5.3 Indirect functions of antibody
  • 1.5.4 Regulation
• 1.6 Tissue damage caused by the immune system
  • 1.6.1 Inflammation: a brief overview
• 1.7 Organization of the immune system: an overview
• 1.8 Conclusions

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Visit the companion website at www.immunologyclinic.com to download cases on these topics.

1.1 Introduction

The immune system evolved as a defence against infectious diseases. Individuals with markedly deficient immune responses, if untreated, succumb to infections in early life. There is, therefore, a selective evolutionary pressure for a really efficient immune system. Although innate systems are fast in response to pathogens, the evolution to adaptive responses provided greater efficiency. However a parallel evolution in pathogens means that all species, plants, insects, fish, birds and mammals, have continued to improve their defence mechanisms over millions of years, giving rise to some redundancies as well as resulting in apparent complexity. The aim of this chapter is to provide an initial description of the molecules involved, moving onto the role of each in the immune processes rather than the more traditional sequence of anatomical structure, cellular composition and then molecular components. It is hoped that this gives a sense of their relationship in terms of immediacy and dependency as well as the parallel evolution of the two immune systems. An immune response consists of five parts:

1. recognition of material recognized as foreign and dangerous;

2. an early innate (non-specific) response to this recognition;

3. a slower specific response to a particular antigen, known as adaptive responses;

4. non-specific augmentation of this response;

5. memory of specific immune responses, providing a quicker and larger response when that particular antigen is encountered the second time.

Innate immunity, though phylogenetically older and important in terms of speed of a response, is less efficient. Humoral components (soluble molecules in the plasma) and cells in blood and tissues are involved. Such responses are normally accompanied by inflammation and occur within a few hours of stimulation (Table 1.1).

Table 1.1 Components of innate and adaptive immunity

Features	Innate	Adaptive
Foreign molecules recognized	Structures shared by microbes, recognized as patterns (e.g. repeated glycoproteins) PAMPs	Wide range of very particular molecules or fragments of molecules on all types of extrinsic and modified self structures
Nature of recognition receptors	Germline encoded – limited PRRs	Somatic mutation results in wide range of specificities and affinities
Speed of response	Immediate	Time for cell movement and interaction between cell types
Memory	None	Efficient
Humoral components	Complement components	Antibodies
Cellular components	Dendritic cells, neutrophils, macrophages, NK cells, NKT cells, B1 cells, epithelial cells, mast cells	Lymphocytes – T (Th1, Th2, Th17, T regs) B
	iNKT cells, γδ T cells

Adaptive immune responses are also divided into humoral and cellular responses. Adaptive humoral responses result in the generation of antibodies reactive with a particular antigen. Antibodies are proteins with similar structures, known collectively as immunoglobulins (Ig). They can be transferred passively to another individual by injection of serum. In contrast, only cells can transfer cellular immunity. Good examples of cellular immune responses are the rejection of a graft by lymphoid cells as well as graft-versus-host disease, where viable transferred cells attack an immunologically compromised recipient that is unable to fight back.

Antibody-producing lymphocytes, which are dependent on the bone marrow, are known as B cells. In response to antigen stimulation, B cells will mature to antibody-secreting plasma cells. Cellular immune responses are dependent on an intact thymus, so the lymphocytes responsible are known as thymus-dependent (T) cells. The developmental pathways of both cell types are fairly well established (Fig. 1.1).

Fig. 1.1 Development of different types of blood from a pluripotential stem cell in the bone marrow. The developmental pathway for natural killer (NK) cells is shown separately because it is thought NK cells may develop in both the thymus and the bone marrow.

The recognition phase is common to both adaptive and innate immunity. It involves professional cells, known as classical dendritic cells, that recognize general pathogen features or specific antigenic molecules, process the antigens and present antigen fragments to the other cells of the immune systems as well as initiating non-specific inflammation to the pathogen. In the effector phase, neutrophils and macrophages (innate immunity) and antibodies and effector T lymphocytes (adaptive immunity) eliminate the antigen.

In terms of disease, like other organs, the immune system may fail (immunodeficiency), may be come malignant (lymphoid malignancies) or produce aberrant responses (such as in autoimmunity or allergy). This chapter describes the normal immune system in order to lay the basis for discussing these ways in which it can go wrong and so cause disease.

1.2 Key molecules

Many types of molecules play vital roles in both phases of immune responses; some are shared by both the innate and the adaptive systems. Antigens are substances that are recognized by immune components. Detection molecules on innate cells recognize general patterns of ‘foreignness’ on non-mammalian cells, whereas those on adaptive cells are specific for a wide range of very particular molecules or fragments of molecules. Antibodies are not only the surface receptors of B cells (BCRs) that recognize specific antigens, but, once the appropriate B cells are activated and differentiate into plasma cells, antibodies are also secreted into blood and body fluids in large quantities to prevent that antigen from causing damage. T cells have structurally similar receptors for recognizing antigens, known as T-cell receptors (TCRs). Major histocompatibility complex (MHC) molecules provide a means of self-recognition and also play a fundamental role in T lymphocyte effector functions. Effector mechanisms are often dependent on messages from initiating or regulating cells; soluble mediators, which carry messages between cells, are known as interleukins, cytokines and chemokines.

1.2.1 Molecules recognized by immune systems

Foreign substances are recognized by both the innate and adaptive systems, but in different ways, using different receptors (see section 1.2.2). The innate system is activated by ‘danger signals’, due to pattern recognition receptors (PRRs) on dendritic cells recognizing conserved microbial structures directly, often repeated polysaccharide molecules, known as pathogen-associated molecular patterns (PAMPs). Toll-like receptors (receptors which serve a similar function to toll receptors in drosophila) make up a large family of non-antigen-specific receptors for a variety of individual bacterial, viral and fungal components such as DNA, lipoproteins and lipopolysaccharides. Activation of dendritic cells by binding to either of these detection receptors leads to inflammation and subsequently activation of the adaptive system.

Phagocytic cells also recognize particular patterns associated with potentially damaging materials, such as lipoproteins and other charged molecules or peptides.

Traditionally, antigens have been defined as molecules that interact with components of the adaptive system, i.e. T- and B-cell recognition receptors and antibody. An antigenic molecule may have several antigenic determinants (epitopes); each epitope can bind with an individual antibody, and a single antigenic molecule can therefore provoke many antibody molecules with different binding sites. Some low-molecular-weight molecules, called haptens, are unable to provoke an immune response themselves, although they can react with existing antibodies. Such substances need to be coupled to a carrier molecule in order to have sufficient epitopes to be antigenic. For some chemicals, such as drugs, the carrier may be a host (auto) protein. The tertiary structure, as well as the amino acid sequence, is important in determining antigenicity. Pure...